Explore the vast range of titles available.

Chimeric Antigen Receptor (CAR) T-cell therapy has demonstrated efficacy in children and young adult patients with acute lymphoblastic leukemia (ALL). The purpose of our study was to investigate thymus size changes after CAR T-cell therapy, explore the associated clinical conditions, and assess survival differences of patients who underwent CAR T-cell therapy, we conducted a single-center retrospective study of children and young adult patients who underwent CAR T-cell therapy for ALL between April 2015 and October 2023.We measured the volume of the thymus on pre- and post-CAR T-cell chest CT scans of 20 patients (median [IQR] age, 18[11] years; 11 females). We divided patients into two groups, those who did (group 1) or did not (group 2) demonstrate increase in thymus size after therapy. Clinical and survival data were collected. We used the Wilcoxon signed-rank test or Fisher’s exact test for group comparisons and analyzed event-free survival data. Seven of 20 patients (35%, group 1) showed increase in thymus volume (pre- vs. post-CAR T-cell thymus volume; 5.01 [2.18] cm³ vs. 20.87 [19.86] cm³, p = 0.01), while 13 patients (65%, group 2) showed no increase in thymus volume (pre- vs. post-CAR T-cell thymus volume; 3.01 [13.42] cm³ vs. 2.09 [8.34] cm³, p = 0.01). Patients in group 1 were younger (12 [8] years vs. 19[10] years, p = 0.028) and showed a higher rate of event-free survival compared to those in group 2 (p = 0.003). In children and young adults with ALL, increased thymus size after CAR T-cell therapy was associated with younger age and improved clinical outcomes.

Standard testing for disease evaluation in B-cell acute lymphoblastic leukemia (B-ALL) includes examination of the bone marrow and cerebrospinal fluid. Radiographic or functional imaging are indicated when clinical signs of non-CNS extramedullary disease are present but are not standard in the relapsed/refractory setting. We describe two cases of patients with relapsed/refractory B-ALL with prior exposure to blinatumomab and/or inotuzumab ozogamicin presenting for CAR-T cell treatment. Both patients were thought to only have minimal residual disease (MRD) at the pre-CAR disease assessment, with MRD of 6,648 (0.66%) and 100 (0.01%) cells per million cells, respectively, as measured by next-generation sequencing (NGS) in their bone marrows. Both patients for distinct reasons unrelated to non-CNS extra-medullary (EM) symptoms had PET-MRIs prior to lymphodepletion and CAR T cell infusion. In both cases patients were found to have significant bulky subclinical EM disease that required changes in clinical management. In the newly-emergent era of antigen-targeted immunotherapy, it is foundational that incidence and relapse patterns following targeted therapy are well-understood. Herein we contribute to a growing body of literature addressing this fundamental clinical gap and highlight a future role for formal prospective imaging studies to better establish response, toxicity and relapse patterns following CAR-T cell therapy in EM B-ALL.

Background: Chimeric antigen receptor (CAR) T cell therapy is an effective salvage therapy for pediatric relapsed B-cell acute lymphoblastic leukemia (B-ALL), yet is challenged by high rates of post-CAR relapse. Literature describing specific relapse patterns and extramedullary (EM) sites of involvement in the post-CAR setting remains limited, and a clinical standard for post-CAR disease surveillance has yet to be established. We highlight the importance of integrating peripheral blood minimal residual disease (MRD) testing and radiologic imaging into surveillance strategies, to effectively characterize and capture post-CAR relapse. Main body: Here, we describe the case of a child with multiply relapsed B-ALL who relapsed in the post-CAR setting with gross non-contiguous medullary and EM disease. Interestingly, her relapse was identified first from peripheral blood flow cytometry MRD surveillance, in context of a negative bone marrow aspirate (MRD <0.01%). Positron emission tomography with 18F-fluorodeoxyglucose revealed diffuse leukemia with innumerable bone and lymph node lesions, interestingly sparing her sacrum, the site of her bone marrow aspirate sampling. Conclusions: We highlight this case as both peripheral blood MRD and 18F-fluorodeoxyglucose positron emission tomography imaging were more sensitive than standard bone marrow aspirate testing in detecting this patient’s post-CAR relapse. Clinical/Biologic Insight: In the multiply relapsed B-ALL setting, where relapse patterns may include patchy medullary and/or EM disease, peripheral blood MRD and/or whole body imaging, may carry increased sensitivity at detecting relapse in patient subsets, as compared with standard bone marrow sampling.

BackgroundChimeric antigen receptor (CAR) therapy and hematopoietic stem cell transplantation (HSCT) are therapeutics for relapsed acute lymphocytic leukemia (ALL) that are increasingly being used in tandem. We identified a non-physiologic CD19+/CD3+ T-cell population in the leukapheresis product of a patient undergoing CAR T-cell manufacturing who previously received a haploidentical HSCT, followed by infusion of a genetically engineered T-cell addback product. We confirm and report the origin of these CD19+/CD3+ T cells that have not previously been described in context of CAR T-cell manufacturing. We additionally interrogate the fate of these CD19-expressing cells as they undergo transduction to express CD19-specific CARs.Main bodyWe describe the case of a preteen male with multiply relapsed B-ALL who was treated with sequential cellular therapies. He received an αβ T-cell depleted haploidentical HSCT followed by addback of donor-derived T cells genetically modified with a suicide gene for iCaspase9 and truncated CD19 for cell tracking (RivoCel). He relapsed 6 months following HSCT and underwent leukapheresis and CAR T-cell manufacturing. During manufacturing, we identified an aberrant T-cell population dually expressing CD19 and CD3. We hypothesized that these cells were RivoCel cells and confirmed using flow cytometry and PCR that the identified cells were in fact RivoCel cells and were eliminated with iCaspase9 activation. We additionally tracked these cells through CD19-specific CAR transduction and notably did not detect T cells dually positive for CD19 and CD19-directed CARs. The most likely rationale for this is in vitro fratricide of the CD19+ ‘artificial’ T-cell population by the CD19-specific CAR+ T cells in culture.ConclusionsWe report the identification of CD19+/CD3+ cells in an apheresis product undergoing CAR transduction derived from a patient previously treated with a haploidentical transplant followed by RivoCel addback. We aim to bring attention to this cell phenotype that may be recognized with greater frequency as CAR therapy and engineered αβhaplo-HSCT are increasingly coupled. We additionally suggest consideration towards using alternative markers to CD19 as a synthetic identifier for post-transplant addback products, as CD19-expression on effector T cells may complicate subsequent treatment using CD19-directed therapy.

Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal paediatric tumours of the central nervous system 1 . We have previously shown that the disialoganglioside GD2 is highly expressed on H3K27M-mutated glioma cells and have demonstrated promising preclinical efficacy of GD2-directed chimeric antigen receptor (CAR) T cells 2 , providing the rationale for a first-in-human phase I clinical trial (NCT04196413). Because CAR T cell-induced brainstem inflammation can result in obstructive hydrocephalus, increased intracranial pressure and dangerous tissue shifts, neurocritical care precautions were incorporated. Here we present the clinical experience from the first four patients with H3K27M-mutated DIPG or spinal cord DMG treated with GD2-CAR T cells at dose level 1 (1 × 10 6 GD2-CAR T cells per kg administered intravenously). Patients who exhibited clinical benefit were eligible for subsequent GD2-CAR T cell infusions administered intracerebroventricularly 3 . Toxicity was largely related to the location of the tumour and was reversible with intensive supportive care. On-target, off-tumour toxicity was not observed. Three of four patients exhibited clinical and radiographic improvement. Pro-inflammatory cytokine levels were increased in the plasma and cerebrospinal fluid. Transcriptomic analyses of 65,598 single cells from CAR T cell products and cerebrospinal fluid elucidate heterogeneity in response between participants and administration routes. These early results underscore the promise of this therapeutic approach for patients with H3K27M-mutated DIPG or spinal cord DMG. A phase I dose-escalation trial of GD2-CAR T cells in children and young adults with diffuse midline gliomas to assess the feasibility of manufacturing, safety and tolerability, and to preliminarily assess efficacy.

H3K27M-mutant diffuse midline gliomas (DMGs) express high levels of the disialoganglioside GD2 (ref. 1 ). Chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) eradicated DMGs in preclinical models 1 . Arm A of Phase I trial no. NCT04196413 (ref.  2 ) administered one intravenous (IV) dose of autologous GD2-CART to patients with H3K27M-mutant pontine (DIPG) or spinal DMG (sDMG) at two dose levels (DL1, 1 × 10 6  kg − 1 ; DL2, 3 × 10 6  kg −1 ) following lymphodepleting chemotherapy. Patients with clinical or imaging benefit were eligible for subsequent intracerebroventricular (ICV) intracranial infusions (10–30 × 10 6 GD2-CART). Primary objectives were manufacturing feasibility, tolerability and the identification of maximally tolerated IV dose. Secondary objectives included preliminary assessments of benefit. Thirteen patients enroled, with 11 receiving IV GD2-CART on study ( n  = 3 DL1 (3 DIPG); n  = 8 DL2 (6 DIPG, 2 sDMG)). GD2-CART manufacture was successful for all patients. No dose-limiting toxicities occurred on DL1, but three patients experienced dose-limiting cytokine release syndrome on DL2, establishing DL1 as the maximally tolerated IV dose. Nine patients received ICV infusions, with no dose-limiting toxicities. All patients exhibited tumour inflammation-associated neurotoxicity, safely managed with intensive monitoring and care. Four patients demonstrated major volumetric tumour reductions (52, 54, 91 and 100%), with a further three patients exhibiting smaller reductions. One patient exhibited a complete response ongoing for over 30 months since enrolment. Nine patients demonstrated neurological benefit, as measured by a protocol-directed clinical improvement score. Sequential IV, followed by ICV GD2-CART, induced tumour regressions and neurological improvements in patients with DIPG and those with sDMG. We evaluated the use of chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) for H3K27M + diffuse midline glioma (DMG), finding that intravenous administration of GD2-CART, followed by intracranial infusions, induced tumour regressions and neurological improvements in patients with H3K27M-mutant pontine or spinal DMG.

Chimeric antigen receptor (CAR) T cells targeting CD22 (CD22-CAR) provide a therapeutic option for patients with CD22 + malignancies with progression after CD19-directed therapies. Using on-site, automated, closed-loop manufacturing, we conducted parallel Phase 1b clinical trials investigating a humanized CD22-CAR with 41BB costimulatory domain in children and adults with heavily treated, relapsed/refractory (r/r) B-ALL. Of 19 patients enrolled, 18 had successful CD22-CAR manufacturing, and 16 patients were infused. High grade (3–4) cytokine release syndrome (CRS) and immune effector-cell-associated neurotoxicity syndrome (ICANS) each occurred in only one patient; however, three patients experienced immune-effector-cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS). Twelve of 16 patients (75%) achieved CR with an overall 56% MRD-negative CR rate. Duration of response was overall limited (median 77 days), and CD22 expression was downregulated in 4/12 (33%) available samples at relapse. In summary, we demonstrate that closed-loop manufacturing of CD22-CAR T cells is feasible and is associated with a favorable safety profile and high CR rates in pediatric and adult r/r B-ALL, a cohort with limited CD22-CAR reporting.

Informal Science Centers provide educational experiences for people across the country daily. While the terminology is often similar, there are differences between institutions, often determined by mission, organizational structure, and experience. The purpose of this study was to identify shared experiences and unique characteristics of eight informal science centers around the country. The significance of the study was to add to the understanding of informal science educators' responsibilities, organizational structure, decision-making process, and development. Data for the study was collected using qualitative measures through a researcher-created interview, sent to fifteen institutions, after the recommendation from two well-known informal science researchers. Eight organizations agreed to complete the interview process, which was done utilizing a digital platform.The interviews showed most institutions have similar expectations of their educators and their responsibilities. The data indicated educators have large say in determining programming and outreach direction, often based on interest, resources, and state standards. Additionally, the data showed there were significant differences in how institutions structured their educators organizationally.The results of this study show the need for informal science centers to continue to evaluate data to determine best practices. Some institutions seemed to have more efficiently and effectively determined best practices. There should be a continued emphasis on evaluations, both programmatically and personally, as several sites did not have a formal evaluative process.

BackgroundH3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal cancers in children and young adults. Our team previously demonstrated efficacy of GD2-targeting chimeric antigen receptor (GD2-CAR) T-cells in preclinical models of DMG1 and opened a Phase I clinical trial (NCT04196413) treating patients with intravenous (IV) followed by repeated infusions of intracerebroventricular (ICV) GD2-CAR T-cells.2 Encouragingly, 10/12 infused patients experienced neurologic benefit and/or volumetric tumor reductions. However, most patients had disease progression with varying durations of response, including limited duration <5 months (n=4), intermediate duration 5-12 months (n=4), and sustained response >12 months (n=4). To understand the mechanisms of resistance to CAR T-cells in patients, we employed a robust reverse translational platform of high-dimensional analyses of patient samples. Here, we present an in-depth evaluation of immune-mediated CAR T-cell rejection in patients treated on this GD2 CAR T-cell trial.MethodsSingle cell RNA-sequencing (scRNAseq) was conducted on 113 cerebrospinal fluid (CSF) samples from 12 patients, resulting in 614,133 single cells. We also developed and implemented a Humanized Anti-CAR Antibodies (HACA) assay on 332 patient plasma and CSF samples. Statistical analyses included Mann-Whitney and Spearman correlation analysis, as appropriate.ResultsIn scRNAseq data, we identified that GD2-CAR T-cell infusion induces dynamic changes to the immune environment in CSF. Patients with limited response duration associated with increased regulatory T-cells early after IV GD2-CAR infusion (p-value=0.046), while loss of response associated with B-cell expansion early after ICV GD2-CAR infusion (p-value=0.062), statistics by Mann-Whitney U-test. HACA development was associated with increased number of GD2-CAR infusions (p-value=0.0541; Mann-Whitney). Additionally, HACA negatively correlated with peripheral blood CAR T-cell persistence (Spearman correlation coefficient = -0.4840). These findings were orthogonally validated using a cell-free ELISA of HACA. Several B-cell receptor clonotypes emerged after GD2-CAR T-cell therapy and were highly expanded and dominant. Studies are ongoing to identify T-cell-mediated immune rejection.ConclusionsTogether, these data identify immune rejection mechanisms in GD2-CAR T-cell-treated DMG patients, providing insights to optimize this therapy with hope to shift the paradigm of this fatal disease.ReferencesMount CW, Majzner RG, Sundaresh S, Arnold EP, Kadapakkam M, Haile S, Labanieh L, Hulleman E, Woo PJ, Rietberg SP, Vogel H, Monje M, Mackall CL. Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M+ diffuse midline gliomas. Nat Med. 2018 May;24(5):572-579. doi: 10.1038/s41591-018-0006-x. Epub 2018 Apr 16. PMID: 29662203; PMCID: PMC6214371Monje M, Mahdi J, Majzner R, Yeom K, Schultz LM, Richards RM, Barsan V, Song KW, Kamens J, Baggott C, Kunicki M, Lim AS, Reschke A, Mavroukakis S, Egeler E, Moon J, Patel S, Chinnasamy H, Erickson C, Jacobs A, Duh AK, Rietberg SP, Tunuguntla R, Klysz DD, Fowler C, Green S, Beebe B, Carr C, Fujimoto M, Brown AK, Petersen AG, McIntyre C, Siddiqui A, Lepori-Bui N, Villar K, Pham K, Bove R, Musa E, Reynolds W, Kuo A, Prabhu S, Rasmussen L, Cornell TT, Partap S, Fisher PG, Campen CJ, Grant G, Prolo L, Ye X, Sahaf B, Davis KL, Feldman SA, Ramakrishna S, Mackall C. Sequential intravenous and intracerebroventricular GD2-CAR T-cell therapy for H3K27M-mutated diffuse midline gliomas. medRxiv [Preprint]. 2024 Jun 27:2024.06.25.24309146. doi: 10.1101/2024.06.25.24309146. PMID: 38978673; PMCID: PMC11230330